Anti-idiotypes and Immunity

Dr. Ziad Jaradat

Anti-idiotypes and Immunity

The immune system of an individual can make millions of different kinds of antibodies:

Each antibody can in turn be the target of other antibodies that recognize its unique molecular characteristics. By means of such antibody-antibody re actions the immune system interacts with itself.

Networks of reactions seem to modulate the normal immune response, and disorders of the networks may underline autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and myasthenia gravis, which stem from an immunological attack on the body itself.

These interactions, known as idiotype-anti-idiotype reactions, can be exploited to manipulate the immune system.

The possibility could have profound implications for the therapy of a spectrum of illnesses ranging from infections through many kinds of cancer to autoimmune diseases.

The basis of each antibody’s specificity resides at one end of its constituent chains of amino acids.

There are four such chains in an antibody molecule: two identical heavy, or long, chains flanked by two identical light chains, or shorter segments.

Figure (1) shows a map of the antibody molecule including the regions of idiotype, allotype and isotype.

An initial antibody (Ab-1) isolated from the animal’s serum and injected into another animal, will induced a second antibody (Ab-2). The Ab-2 bound only to the Ab-1 and not to other antibodies against which it was tested.

It could therefore be said to recognize the primary antibody’s individuality.

Oudin referred to the unique antigenic determinants on the Ab-1 as its idiotype

For the Ab-2 produced in response to the idiotype he coined the term anti-idiotype.

Other work showed that the immune

system can make various kinds of antibodies in response to an Ab- 1.

Some of them bind not only to the Ab-1 that induced them but also to other antibodies with the same class.

Presumably those second antibodies, which are known as anti-isotypes recognize antigenic determinants in the constant regions of the heavy and light chains of the same class of antibodies.

Another set of antibodies, called anti-allotypes, react with every antibody made by the individual from which the Ab-1 was taken, although not necessarily with antibodies from other individuals.

An anti-idiotype, in contrast, was defined as an antibody that is able to react only with the Ab-1 elicited by a single antigen.

The idiotype therefore, must lie in the variable region of the antibody.

Example of production and purification of the anti-idiotypic antibodies

To produce an antibody against hepatitis B viral antigen

A rabbit was injected with purified antigen from HB virus

Collect the serum after several injections and purify the antibodies against he HB virus. This antibody is designated as Ab-1.

Inject purified Ab-1 in goat

The serum obtained from the goat will contain:

preexisting antibodies (none specific)contains anti-idiotypic antibodiescontains anti-isotypic antibodiescontains anti-allotypic antibodies

Purification and absorption of the antibodies

One column has antibodies that bind both allotypic and isotypic antibodies but not the idiotypic antibodies and the preexisting antibodies

Column 2 has antibodies that bound the anti-idiotypic antibodies so when the serum passed through it captures the anti-idiotypic antibodies and let the preexisting antibodies pass through.

Column 2 then flushed with a buffer that elutes the pure form of anti-idiotypic antibodies.

These anti-idiotypic antibodies mimic the original antigen therefore, they are called surrogate antigens.

This process is depicted in the following diagram.

Types of anti-idiotypic antibodies

Ab2α; are set of antibodies that idiotopes distinct from the antigen binding site of Ab-1. The binding of these antibodies to Ab1 does not interfere with the antigen binding capacity of Ab1.

Ab2 β; carries an internal image of the nominal antigen. They constitute about only 15-20 % of the total Ab2. They interfere with binding of the Ag to the Ab1(complete inhibition) . They bear an internal image of the antigen.

Ab2 γ; like the Ab2 β recognizes epitopes within the nominal antigen binding site and can inhibit the binding of Ag to Ab1 but do not bear an internal image of the antigen, thus they partially blocks binding of Ag to Ab1.

Anti-idiotypic vaccines

EXAMPLE OF AN EXPERIMENT human antibody against HB antigen is

injected into a rabbit that makes Ab-2. Ab-2 is injected into a mouse or a chimp to

make Ab3.

Ab-2 is similar in shape to the antigenAb-3 is similar in specificity to Ab1Now Ab-3 was able to protect the chimp

against a real infection of HB

Advantages of Anti-idiotypic antibodies

Anti-idiotypic antibodies offer certain advantages over the conventional vaccines;

Ids would eliminate the complications of using killed, attenuated or subunit vaccines thus eliminates the dangers of using these pathogens

A major advantage is their ability to trigger B and T cell immunity. They induce the generation of the T-helper memory cells which results in long lasting immunity. This property may confer immunity on neonates who do not respond to conventional immunotherapy.

One of the most advantages is the use of anti-idiotypic antibodies is mapping antigenic sites or epitopes involved in immune recognition.

Anti-idiotypic antibodies that could prime the host for a desired immune response could be sequenced and computer models could be generated to predict antibody binding sites.

These data could be used to predict immunodominant epitopes on the organism or tumor and lead to the synthesis of better vaccines.

This can be useful in identification of cell surface receptors.

Another method, the idiotypic antibodies can be easily labeled with FITC or electron dens particles so that its target on the cell surface will be identifiable under light microscope.

Disadvantages

Repeated immunization of humans with heterologous serum proteins lead to the development of serum sickness

Vaccination with anti-idiotypic antibodies may not confer a complete protection and may require subsequent exposure to an antigen.

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